Project summary Over two-thirds of the population in the United States and globally are over-weight or obese. The increased risk of chronic diseases among obese, including cardiovascular, respiratory diseases and cancer is well established. However, it was recognized only recently that obesity also increases risk for infectious disease morbidity and mortality. The growing obesity epidemic suggests a large proportion of the population is at risk, but the mechanisms explaining the increased risk of infection among obese are largely unknown. Given the high prevalence of obesity in the population, understanding how molecular and cellular responses vary among obese vs. non-obese can provide important insights into reducing risk and treatment among this susceptible population. Toll-like receptors (TLRs), responsible for pathogen detection, may provide important clues in understanding the relationship between obesity, immune function and the environment. TLRs play a key role in orchestrating the immune response to infections by detecting diverse pathogen-associated molecules from viruses, bacteria, fungi or protozoa and producing cytokines and other inflammatory mediators. Interestingly, recent studies have also revealed that TLR2 and TLR4 mediate immune responses to air pollutants as particulate matter can carry microbes that activate TLRs and trigger inflammatory responses. TLR4 is most studied TLR, but very little is known about the entire spectrum of other TLRs and the role they play in obesity. Furthermore, there are no population-based studies to date systemically examining the effects of obesity on the expression and function of TLRs. We hypothesize that obesity suppresses TLR expression and/or function leading to abnormal responses to pathogens and exogenous agents. We will test our hypothesis using human peripheral blood mononuclear cells (PBMCs) available through the Survey of the Health of Wisconsin, a well-established ongoing annual population-based health survey. PBMCs will be analyzed for TLR1-TLR10 expression (Aim 1). In addition, TLRs inflammatory responses will be analyzed in freshly prepared PBMCs that will be stimulated ex vivo with TLR ligands (Aim 2). To date, no human studies have examined the breadth of TLRs response in obesity. Therefore, the goals of this high-risk/high-reward research are to investigate how obesity alters expression and function of TLRs, and will provide important insight into the mechanisms by which obesity alters human response to pathogens and environmental exposures, and the role of TLRs in driving human sensitivity and response.